INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 19/399,293

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Abstract

Provided herein are compounds of formula (I′): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 2 , Y 3 , L 1 , L 2 , X 1 , X 2 , X 3 , X 4 , X 5 , Q 1 , R 1 , R 2 , R k , R m , and R n are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I′). Also provided herein are methods of inhibiting GYS1 and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Claims (59)

1 . A pharmaceutical composition comprising (i) a compound of formula (I-A):

or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 1 is CH or N;

R x and R z are independently H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x or R z may be optionally substituted with one or more halo;

R y is (i) C 1-6 alkyl, or (ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl;

R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl;

R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b ; and

R b is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 3-10 cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R b is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R b is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy,

wherein the moiety represented by

has a stereochemical configuration of the formula:

and (ii) one or more pharmaceutically acceptable excipients.

2 - 5 . (canceled)

6 . The pharmaceutical composition of claim 1 , wherein the moiety represented by

is selected from the group consisting of

7 . The pharmaceutical composition of claim 1 , wherein the moiety represented by

is selected from the group consisting of

8 - 36 . (canceled)

37 . The pharmaceutical composition of claim 1 , wherein R x is H, fluoro, or methyl, and R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl.

38 . The pharmaceutical composition of claim 1 , wherein R k is H or halo.

39 - 41 . (canceled)

42 . The pharmaceutical composition of claim 1 , wherein R 2 is selected from the group consisting of

43 . The pharmaceutical composition of claim 1 , wherein R 2 is

44 - 53 . (canceled)

54 . A pharmaceutical composition comprising (i) a compound selected from the group consisting of

or a pharmaceutically acceptable salt of any of the foregoing; and

(ii) one or more pharmaceutically acceptable excipients.

55 - 90 . (canceled)

91 . The pharmaceutical composition of claim 1 , wherein the compound is of formula (I-A3):

or a pharmaceutically acceptable salt of any of the foregoing, wherein

R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein the C 1-6 alkyl is optionally substituted with one or more halo; and

the moiety represented by

has a stereochemical configuration of the formula:

92 . The pharmaceutical composition of claim 1 , wherein the compound of formula (I-A) is (2S,4R)-1-(2-(1H-1,2,3-triazol-5-yl)acetyl)-4-fluoro-N—((S)-(4-isopropylphenyl)(phenyl)methyl)pyrrolidine-2-carboxamide having the structure